Understanding Pain in hEDS

See below for Low-Dose Naltrexone

Pain is one of the most common and complex symptoms in people living with hypermobile Ehlers-Danlos syndrome (hEDS). It can affect almost every part of the body and often interferes with daily activities, emotional well-being, and overall quality of life. Unlike acute pain caused by injury or illness, pain in hEDS tends to be chronic, multifactorial, and difficult to treat with a one-size-fits-all approach.

Sources of Pain in hEDS

Pain in hEDS comes from many different systems in the body, often interacting and amplifying one another. Below are the main categories.

Musculoskeletal Pain

Due to joint hypermobility, ligaments and tendons can’t support the joints properly. This leads to

• Recurrent subluxations or dislocations

• Soft tissue injury

• Muscle overuse and joint instability during daily movement

Myofascial Pain

This type of pain originates in muscles and surrounding tissues. It often involves

• Trigger points (painful muscle knots)

• Muscle spasms caused by instability or compensation for weak joints

Neuropathic Pain

Some people with hEDS experience pain described as burning, tingling, electric-like, or sharply stabbing. It may involve

• Peripheral nerve damage or compression: This can occur when unstable joints irritate or press on nearby nerves. The resulting pain may feel like shooting zaps, a sudden jolt of electricity, or a deep ache that follows the path of the affected nerve. Numbness, tingling, or muscle weakness may accompany the pain.

• Small fiber neuropathy (SFN): Studies show that many people with hEDS have SFN, a condition involving degeneration of small nerve fibers. Clinical findings include reduced intraepidermal nerve fiber density and symptoms such as

  • Sharp, shooting, or burning sensations

  • Randomly located or multifocal nerve pain

  • Entrapment and peripheral neuropathies, which are common in hEDS, especially around unstable joints

  • Altered sensory thresholds, especially in painful joints

Sharp nerve pain at random points on the body is frequently reported. This pain may occur independently of injury and is often unpredictable in timing and location. The GeneReviews guideline by the University of Washington notes that chronic pain in hEDS is often neuropathic in nature and that peripheral neuropathies are a frequent contributor.

Central Sensitization

Over time, chronic pain can cause the brain and spinal cord to become oversensitive to pain signals. This process can lead to

• Widespread pain: Pain that is felt throughout multiple regions of the body—not just in one area or joint. This type of pain is usually diffuse and persistent, and may shift locations or feel deep and aching. It is commonly associated with central sensitization, where the nervous system amplifies normal pain signals.

• Exaggerated responses to touch or pressure

• Symptoms similar to fibromyalgia: Widespread musculoskeletal pain; Fatigue, even after rest; Sleep disturbances, including non-restorative sleep; Cognitive issues ("brain fog") such as trouble concentrating or memory lapses; Increased sensitivity to touch, pressure, cold, or noise; Tender points or areas of the body that are unusually sensitive to pressure

• Amplification of peripheral pain signals, such as those from nerve injury or joint instability

• Unpredictable pain distribution, including sharp pain in seemingly unrelated or uninjured areas

Central sensitization is believed to be a major factor in hEDS-related pain and may explain why many patients experience both nerve-related and widespread pain symptoms.

Headache Pain

People with hEDS often report

• Tension-type headaches

• Migraines, sometimes related to cervical spine instability

• Sinus headaches, due to

  • mast cell activation syndrome

  • allergies

  • structural contributors: Connective tissue fragility in hEDS can affect the nasal passages and sinus drainage, making some individuals more prone to chronic sinus infections, poor sinus drainage, nasal valve collapse, or deviated septums.

• Dysautonomia (especially POTS) and Neurovascular Sensitivity: can heighten pain sensitivity and vascular congestion, which may worsen sinus pressure and contribute to headache symptoms.

Visceral Pain

Pain can also come from internal organs due to

• Gastrointestinal issues (like IBS or reflux)

• Pelvic pain

• Bladder dysfunction

• Other Contributors

Other Contributors

Chronic pain is often worsened by

• Fatigue

• Sleep disturbance

• Anxiety and depression

These factors can heighten pain sensitivity and reduce coping ability.

Possible Treatments for Pain in hEDS

Treating pain in hEDS is often challenging and requires a personalized, multidisciplinary approach. There is no single solution, but many options can be combined to help reduce pain and improve quality of life.

Physical and Occupational Therapy

This is a cornerstone of hEDS treatment. Therapies may include

• Core strengthening

• Proprioception training

• Joint stabilization exercises

These therapies help improve function and prevent further injury.

Bracing and Assistive Devices

Helpful for preventing injury and supporting unstable joints. This may include

• Splints (medical devices used to support, stabilize, or protect joints and soft tissues)

  • finger

  • thumb

  • wrist

  • ankle

  • knee

  • custom

• Orthotics (custom-made or pre-fabricated medical devices worn inside shoes)

• Braces (medical device designed to support, stabilize, protect, or restrict movement in a joint or body part - less rigid than a splint)

  • knee

  • neck

  • wrist

  • thumb

  • elbow

  • ankle

  • torso/rib

  • back/pelvis

• Mobility aids

  • canes

  • crutches

  • walkers

  • wheelchairs

  • scooters

Medications

Although medications rarely eliminate the pain entirely, they can help manage symptoms

• Non-steroidal anti-inflammatory (NSAID) medications (both prescription and OTC) and acetaminophen for inflammation or injury

• Neuropathic agents (e.g., duloxetine, gabapentin, amitriptyline) for nerve-related or widespread pain

• Muscle relaxants – occasionally used for acute muscle spasm; some may be used daily under supervision, but long-term use is limited by side effects and risk of tolerance.

• Opioids – reserved for severe, refractory pain, due to the risks of side effects and dependency

• Low-dose naltrexone (LDN) – showing promise in fibromyalgia and chronic pain (see below)

Behavioral and Psychological Therapies

These therapies help patients manage the emotional and neurological aspects of pain.

• Cognitive Behavioral Therapy (CBT)

• Pain education

• Strategies for stress reduction, sleep, and emotional regulation

Complementary Therapies

Many patients report benefit from

• Acupuncture

• Saline trigger point injections: Saline trigger point injections are sterile saltwater injections into painful muscle knots to relieve tension and pain.

• Massage

• TENS (transcutaneous electrical nerve stimulation)

Surgical Interventions

Sometimes surgery is needed for severe joint instability, but

• Results are often mixed.

• Surgery is only recommended after other treatments fail because hEDS involves fragile tissues and higher complication risks.

Experimental or Theoretical Options

 These treatments lack strong evidence but are being explored

• Prolotherapy: Injections of dextrose or irritants to stimulate tissue repair

• Laser therapy: Low-level laser therapy (LLLT) for inflammation and healing

• Medical marijuana or CBD: Used anecdotally for pain, sleep, and nausea relief

• Suzetrigine (VX-548): A novel drug that blocks peripheral Nav1.8 sodium channel

  • May help with

    • Neuropathic pain

    • Myofascial or soft tissue pain

    • Musculoskeletal pain from subluxations

  • Limitations include lack of evidence in hEDS and limited benefit for central sensitization

Causes and Treatments for Pain

Pain Management Tools for Chronic Conditions

While not hEDS-specific, these evidence-based tools offer helpful strategies.

• Tame the Beast – Educational pain neuroscience videos

• Pathways Pain Relief – A guided app using CBT and mindfulness for chronic pain

• Curable – App combining education, journaling, meditation, and CBT-based pain approaches

Summary

Pain in hypermobile Ehlers-Danlos syndrome (hEDS) is widespread, chronic, and often difficult to manage. It arises from multiple overlapping sources, including joint instability, muscle overuse, nerve dysfunction, and altered nervous system processing. Individuals may experience musculoskeletal, neuropathic, myofascial, visceral, and headache-related pain. Central sensitization—a condition where the nervous system becomes hypersensitive—can further amplify pain and contribute to symptoms like widespread discomfort, fatigue, and cognitive difficulties.

Effective pain management in hEDS requires a personalized, multidisciplinary approach. Core treatments include physical and occupational therapy, joint bracing, medications for nerve and muscle pain, and psychological support. Complementary therapies, such as dry needling, massage, and low-dose naltrexone, may also offer relief. While surgery is sometimes considered for joint instability, it is used cautiously. Experimental treatments like prolotherapy and novel pain medications are under investigation but lack strong evidence in hEDS. Because pain in hEDS is complex and multifactorial, care must be holistic, flexible, and patient-centered.

Low-Dose Naltrexone (LDN)

Low-dose naltrexone (LDN) is an emerging off-label option for people with widespread pain, fatigue, and central sensitization—features common in hEDS.

What is it?

• A very low dose (1.5–4.5 mg) of the drug naltrexone, traditionally used in much higher doses for opioid or alcohol dependence.

• In low doses, it works very differently, modulating pain and inflammation through unique mechanisms.

• Must be obtained at a compounding pharmacy.

• Often is not covered by insurance due to being prescribed off-label. Off-label prescribing is when a healthcare provider prescribes a medication for a use, dose, or population that is not specifically approved by the FDA but is supported by clinical judgment or evidence from research.

How might it help in hEDS?

• LDN is not a standard therapy for hEDS, but it is increasingly used off-label for chronic pain conditions involving central sensitization, such as fibromyalgia, which shares overlapping features with hEDS.

• Proposed mechanisms

  • Inhibition of microglial activation in the central nervous system

  • Toll-like receptor 4 (TLR4) antagonism

  • Reduction of neuroinflammation, possibly helping to dampen pain amplification and brain fog

• Patients often report improvements in

  • Chronic widespread pain

  • Fatigue

  • Sleep quality

  • Cognitive clarity

Evidence base

• Evidence for LDN in hEDS specifically is limited to anecdotal reports and clinician experience.

• However, systematic reviews and meta-analyses show modest benefit in fibromyalgia and related centralized pain conditions, with a good safety profile.

• Most published studies are small or preliminary; high-quality randomized controlled trials in hEDS are currently lacking.

Tolerability

• LDN is generally well-tolerated.

• May have mild and temporary side effects such as vivid dreams or sleep disruption early on.

Formulations

Because commercial manufacturers do not produce tablets in low doses, LDN must be specially prepared by compounding pharmacies. Common formulations include

• Capsules – The most typical option, often filled with microcrystalline cellulose or another neutral filler. Available in precise strengths (e.g., 1.5 mg, 3 mg, 4.5 mg).

• Tablets – Less commonly compounded but sometimes preferred for patients who have trouble swallowing capsules.

• Liquid formulations – Useful for those who require very gradual dose titration (e.g., starting below 1 mg and increasing slowly). Allows for flexible adjustment in 0.1–0.5 mg increments.

• Sublingual drops or lozenges – Occasionally used when gastrointestinal absorption is a concern, though less standardized.

• Topical creams – An experimental option prepared by some pharmacies, typically for patients who cannot tolerate oral forms; evidence is minimal.

Because inactive ingredients vary between pharmacies, patients with sensitivities to dyes, fillers, or excipients (inactive ingredients) may need to request specific formulations. Prescribers can work with the compounding pharmacist to adjust both dosage and formulation to the patient’s needs.

Insurance and Prescription Access

• Insurance coverage is inconsistent. Many insurers consider LDN experimental or non-essential due to its off-label use and will not reimburse for compounded versions.

• Prior authorization or appeal letters from a provider may be required for coverage, and even then, success varies by plan.

• Compounding pharmacies are typically required because low-dose tablets are not commercially manufactured. Prices can range from $30–90/month depending on formulation and location.

• Patients should

  • Ask whether their prescriber can fax the prescription directly to a known compounding pharmacy.

  • Inquire about discount programs or bulk pricing through pharmacies.

  • Save receipts for out-of-pocket costs, which may be reimbursable through FSA/HSA accounts.

• Some patients also find better prices at online or mail-order compounding pharmacies, though quality and licensing should be verified.